Short-term exposure to stressful, aversive stimuli elicits a variety of adaptive physiological and behavioral responses, and chronic exposure to stress can evoke useful, adaptive responses as well. However, chronic exposure to stress also has been implicated in the development of many pathological conditions, including psychiatric disorders, and schizophrenia. In order to elucidate the central component of stress-induced abnormalities, the application will examine the impact of stress on central noradrenergic transmission, particularly the NE- containing neurons of the LC. Recently the investigators observed that exposure to chronic cold increased by 2-fold the ability of a subsequent acute stressor to release NE, a phenomenon that has been termed "sensitization" when observed in other systems. However, little is known about the impact of chronic stress (i.e., as a result of its quality, intensity, and duration) or whether a given stress-induced change may be adaptive or maladaptive. Hence, the project proposes to systematically explore the relation between stress and its effects on LC neurons as well as the functional significance of those effects. In addition, it is planned to study the basic neurobiology of LC neurons, in particular, the nature of the heterosynaptic input to LC terminals and the rate of TH transport in these neurons. Four specific aims are proposed: First, the impact of chronic stress on the synthesis and release of NE in response to a subsequent acute stress will be further characterized. Second, the mechanisms underlying these interactions will be examined by focusing on changes in NE synthesis, release, and inactivation, and by examining both autoreceptor and heteroreceptor input. Third, the application plans to explore the synthesis and transport of TH, the rate-limiting enzyme in NE synthesis. Finally, changes in the electrophysiology of LC neurons during acute and chronic stress will be investigated. The longer-term objectives of this project are to provide new insights into the basic neurobiology of LC neurons and the psychopathology that develops from chronic stress.